Effect Of Dose Intensity Research Articles

MDB-100. RETROSPECTIVE ANALYSIS OF CUMULATIVE DOSING OF CHEMOTHERAPY AGENTS AND THE EFFECT ON SURVIVAL IN PATIENTS WITH AVERAGE RISK MEDULLOBLASTOMA TREATED ON CHILDRENS ONCOLOGY GROUP STUDY ACNS0331

Abstract BACKGROUND Although survival outcomes for average risk (AR) medulloblastoma remain good, patients may experience significant acute and long-term toxicities from therapy. To evaluate the effect of dose modifications among children with AR medulloblastoma, we examined the effect of cumulative chemotherapy dose on overall and event-free survival. METHODS We retrospectively examined the association between the proportion of scheduled chemotherapy dose received on survival outcomes (OS and EFS) using Cox regression models and log-rank tests for patients treated on ACNS0331. We evaluated all chemotherapy agents for the group as a whole and within the four major subgroups. Dose intensity was analyzed continuously and categorically (>75% or <75% of planned dose) for each agent. RESULTS 274 evaluable children (medulloblastoma by methylation, received standard dose craniospinal radiation and chemotherapy) were followed for a median of 9.3 years (range, 7.0-10.4 years). Vincristine and cisplatin showed the most variable dose intensity (25.2% and 31.8% of patients received <75% of expected dosing, respectively). Cyclophosphamide and lomustine were not examined due to low dose variability (17.2% and 11.7%, respectively). The effect of dose intensity was evaluated in 235 patients who completed planned therapy. Molecular subgroup remained a significant predictor of outcome in AR medulloblastoma (EFS (p=0.012) and OS (p=0.008)). Although survival curves were lower for less dose intense treatments, no significant difference in EFS or OS was found due to reduced dose intensity for vincristine (p=0.36 EFS, p=0.35 OS) or cisplatin (p=0.49 EFS, p=0.52 OS). The hazard ratio [95% confidence interval] for chemotherapy proportion and EFS was 0.998[0.977-1.019] (vincristine) and 0.989[0.966-1.012] (cisplatin). There was no difference in the effect of dose reductions by molecular subgroup. CONCLUSIONS Moderate reductions in vincristine and cisplatin dose intensity do not significantly affect survival in AR medulloblastoma. It is unknown whether this reduction would reduce chemotherapy-related toxicity.

Dose-dense neoadjuvant chemotherapy of operable and locally advanced inoperable triple negative breast cancer: First results of single-centre prospective trial

Introduction. Neoadjuvant chemotherapy (NACT) is the standard of care for II–III stages of TN BC. Complete pathomorphological response (pCR) is associated with a signifiant increase in event-free and overall survival. In addition, in the absence of pCR, post-neoadjuvant adjuvant therapy is prescribed, while if pCR is achieved, additional treatment is not carried out. Despite a large number of studies on NACT of TN BC, different NACT regimens in various clinical trials make it diffiult to interpret their results.Objective. To investigate the effiacy of 4ddAC followed by 12 weekly cycles of paclitaxel and carboplatin in TN BC (according to the RCB system and the frequency of pCR); determine the predictive factors for the effectiveness of this chemotherapy regimen, and the effect of dose intensity on the pCR rate.Methods. This prospective study included 154 patients with TN breast cancer who received dose-dence neoadjuvant chemotherapy from January 2017 to March 2022.Results. PCR rate was 53.25 % (n = 82), RCB 0–I was 66.88 % (n = 103), disease progression was observed in 3.25 % (n = 4). The frequency of germline mutations in the BRCA1/2 genes was 21.43 % (n = 33). The most common mutation was BRCA1 5382insC – 63.64 % (n = 21) of all BRCA1/2 mutations. Rare mutations detected by NGS accounted for 30.3 % (n = 10). The only factor associated with a signifiant increase in the pCR rate was age ≤50 years (p = 0.010), there was a trend towards an increase pCR rate in the subgroups T1–2 (p = 0.052) and BRCA1/2 mut (p = 0.080). There was no effect of the dose intensity on the achievement of pCR.Conclusions. This retrospective analysis is the largest study evaluating the effiacy of 4 ddAC followed by 12 PC in NACT TN BC. The regimen allows to achieve a high frequency of pCR, despite the large proportion of patients with locally advanced breast cancer. The high frequency of rare mutations in the BRCA1/2 genes and the potential therapeutic signifiance of this marker in residual disease treatment dictates the need for NGS in all patients with TN in breast cancer.

The influence of adjuvant chemotherapy dose intensity on overall survival in resected colon cancer: a multicentered retrospective analysis

BackgroundColorectal cancer remains the second leading cause of cancer death in North America. Fluorouracil and oxaliplatin based adjuvant chemotherapy for resected colon cancer (CC) reduces cancer recurrence, but also causes significant toxicity requiring dose reductions. The effect of dose intensity on survival outcomes is not fully understood and strengthening the evidence supports informed decision making between patients and oncologists.MethodsPatients treated with adjuvant chemotherapy, between 2006 and 2011, for resected colon cancer at four Canadian academic cancer centers were retrospectively analyzed. All patients must have received oxaliplatin with either capecitabine (CAPOX) or 5-FU (FOLFOX). Dose intensity (DI) was calculated as total delivered dose of an individual chemotherapy agent divided by the cumulative intended dose of that agent. The influence of DI on overall survival was examined.ResultsFive hundred thirty-one patients with high-risk stage II or stage III resected CC were eligible and included in the analysis. FOLFOX was the most common regimen (69.6%) with 29.7% of patients receiving CAPOX and 0.7% receiving both therapies. Median follow-up was 36.7 months. The median DI for 5-FU and capecitabine was 100% and 100% with 13.6% and 9.8% of patients receiving ≤ 80% DI, respectively. The median DI of oxaliplatin was 70% with 56.8% of patients receiving ≤ 80% DI. A DI of > 80% for each chemotherapy component was associated with a significant improvement in overall survival compared to those with a DI of ≤ 80% (5-FU HR = 0.23, 95% CI = 0.08–0.65, p = 0.006; capecitabine HR = 0.56, 95% CI = 0.33–0.94, p = 0.026; oxaliplatin HR = 0.52, 95% CI = 0.33–0.82, p = 0.005). Patients with T2 and/or N2 disease with an oxaliplatin DI > 80% had a trend towards improved survival (HR = 0.62, 95% CI = 0.38–1.02, p = 0.06).ConclusionsIn resected CC an adjuvant chemotherapy DI of > 80%, of each chemotherapy agent, is associated with improved overall survival.

Docetaxel dose-intensity effect on overall survival in patients with metastatic castrate-sensitive prostate cancer.

e16501 Background: Several studies assessed the association of docetaxel dose intensity (DI) and efficacy in metastatic castrate-resistant prostate cancer (mCRPC) patients with contradicting conclusions. In this retrospective analysis we will assess whether the docetaxel DI used in patients with metastatic castrate-sensitive prostate cancer (mCSPC) is associated with overall survival (OS). Methods: We have identified all the patients with mCSPC treated at The Ottawa Hospital Cancer Centre that received docetaxel chemotherapy between June 2014 - September 2017. For each patient we calculated the relative dose intensity (RDI) and assessed whether it’s associated with OS using univariate and multivariate cox-proportional hazards analysis. Results: Eighty-0ne patients were included in the analysis. Nineteen patients (23.5%) had their body surface area capped at 2 which resulted with de facto median dose reduction of 7% (IQR 6% - 9%). Ten patients had upfront dose reduction (usually due to significant co-morbidities) with a median dose reduction of 20% (IQR 19.25 – 20.75). Only 35 patients (43.2%) were able to complete the planned treatment with a RDI of at least 90%. After a median follow-up of 29.4 months, 32 patients (39.5%) died. The median OS was 43.9 months. On a univariate analysis RDI and number of cycles of docetaxel received were found to be statistically significant associated with OS. For every 10% decrease in RDI the risk of death increased by 23% (HR 1.23, 95% CI 1.09 – 1.4, P = 0.0011). For every incremental cycle (up to a total of 6) the risk of death decreased by 27% (HR 0.73, 95% CI 0.61- 0.88, P = 0.001). On multivariate analysis we included age, Gleason score, burden of disease, visceral involvement and baseline PSA. Reduced RDI remained the only significant variable associated with OS (HR 1.2, 95% CI 1.04 – 1.39, P = 0.0117). Conclusions: Reduced docetaxel DI administrated to mCSPC patients is associated with worse survival. Therefore unnecessary docetaxel dose reductions, treatments delays and early discontinuation should be avoided. Granulocyte-colony stimulating factor should be considered in order help maintain standard DI.

Retrospective analysis of the effect of CAPOX and mFOLFOX6 dose intensity on survival in colorectal patients in the adjuvant setting.

Despite lack of a true comparative study, the folfox (5-fluorouracil-leucovorin-oxaliplatin) and capox (capecitabine-oxaliplatin) regimens are believed to be similar in their efficacy and tolerability in the treatment of stage iii colorectal cancer. However, that belief has been disputed, because real-life data suggest that the capox regimen is more toxic, leading to more frequent reductions in the delivered dose intensity-thus raising questions about the effect of dose intensity on clinical outcomes. A retrospective data review for two Canadian institutions, the Segal Cancer Centre and the Tom Baker Cancer Centre, considered patients diagnosed with stage iii colorectal cancer during 2006-2013. Primary endpoints were dose intensity and toxicity, with a secondary endpoint of disease-free survival. The study enrolled 180 eligible patients (80 at the Segal Cancer Centre, 100 at the Tom Baker Cancer Centre). Of those 180 patients, 75 received capox, and 105 received mfolfox6. In the capox group, a significant dose reduction was identified for capecitabine compared with 5-fluorouracil in mfolfox6 group (p = 0.0014). Similarly, a significant dose reduction was observed for oxaliplatin in mfolfox6 compared with oxaliplatin in capox (p = 0.0001). Compared with the patients receiving capox, those receiving mfolfox6 were twice as likely to experience a treatment delay of more than 1 cycle-length (p = 0.03855). Toxicity was more frequent in patients receiving mfolfox6 (nausea: 30% vs. 18%; diarrhea: 47% vs. 24%; peripheral sensory neuropathy: 32% vs. 3%). At a median follow-up of 40 months, preliminary data showed no difference in disease-free survival (p = 0.598). Pooled data from both institutions were also separately analyzed, and no significant differences were found. Our results support the use of capox despite a lack of head-to-head randomized trial data.

A Randomised Dose De-Escalation Study of Oral Fludarabine, ±Oral Cyclophosphamide and Intravenous Rituximab As First-Line Therapy of Fit Patients with Chronic Lymphocytic Leukaemia (CLL) Aged ≥65 Years: Final Analysis of Response and Toxicity

BACKGROUND: Fludarabine (F), cyclophosphamide (C) and rituximab (R) gave superior progression free (PFS) and overall survival (OS) versus (vs) FC in the CLL8 Study. The median age in CLL8 was 61 years compared to 72 years for CLL overall. We aimed to assess the safety, tolerability and efficacy of FCR based therapy in elderly patients (pts). METHODS: Previously untreated pts with progressive CLL aged ≥65 were randomised to one of 3 therapy arms: (i) FR5: F 24mg/m2 po D1-5 + R (375mg/m2 cycle 1, 500mg/m2 cycles 2-6) iv D1, (ii) FCR3: F 24mg/m2 po and C 150mg/m2 po D1-3 + R iv D1 or (iii) FCR5: F 24mg/m2 po+ C 150mg/m2 po D1-5 + R iv D1 all at 4 weekly intervals for an intended 6 cycles. Cycles could be delayed up to 2 weeks for grade 3+ toxicity, and if unresolved by 2 weeks, pts were taken off study. All analyses were by intention to treat (ITT) and adjusted for pre-treatment Binet stage. RESULTS: Recruitment of 120 pts was completed in July 2012. 117 fulfilled eligibility and 1 had no treatment or follow-up reducing the cohort to 116. Median age was 71 (range 65-82) years; 78 males (67%) and 39 females (33%). Binet stage was progressive A - 19 (16.2%), B – 55 (47.0%), C – 43 (36.8%). Response data are shown in table 1 and grade 3+ toxicity in table 2. All 6 protocol cycles were completed in 69% but less on FCR5 44% vs FR5 89% and FCR3 76% (p ORR was high in all 3 arms but CR rates were higher with FCR5 (p Toxicity was lower with FR5 compared to FCR3 and FCR5 (p=0.004) (FCR3 vs FCR5 NSS). Dose delay occurred in 43 pts (37%): FR5 12 (32%), FCR3 14 (34%), FCR5 17 (44%) (p=0.653), but early cessation due to toxicity was more common with FCR5 (p CONCLUSIONS: Final analysis shows oral FCR therapy is generally safe and well tolerated in CLL pts aged ≥65 years requiring first-line treatment, when early stopping is utilised if prolonged toxicity occurs. Toxicity was mostly hematological and manageable. Response rates were very high with ORR of 96% and CR rate of 56% (39% not including CRu). Full dose FCR is highly effective and while cessation due to toxicity appears important, a dose intensity effect may exist. Dose reduced FCR provides a balance of effectiveness, safety and tolerability as first-line therapy for fit elderly pts. Disclosures Mulligan:Roche: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi Aventis: Research Funding; Janssen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria. Gill:Roche: Research Funding; Sanofi Aventis: Research Funding. Turner:Roche: Research Funding; Sanofi Aventis: Research Funding. Renwick:Roche: Research Funding; Sanofi: Research Funding. Latimer:Roche: Research Funding; Sanofi: Research Funding. Mackinlay:Roche: Research Funding; Sanofi: Research Funding. Berkahn:Roche: Research Funding; Sanofi: Research Funding. Simpson:Onyx: Honoraria, Research Funding; Celgene: Honoraria; Janssen Cilag: Honoraria. Forsyth:Roche: Research Funding; Sanofi: Research Funding. Harrup:Roche: Research Funding; Sanofi: Research Funding. Kuss:Roche: Research Funding; Sanofi: Research Funding.

Effect of dose intensity and overexpression of topoisomerase iia on survival in patients with locally advanced breast cancer treated with anthracyclines

11512 Background: TopoIIa is a therapeutic target of anthracyclins, its predictive and prognostic value in breast cancer is being evaluated. The aim of this study was to determine the effect of anthracycline dose intensity in terms of overall(OS) and free disease survival (DFS) in patients with over expressing TopoIIa. Methods: TopoIIa expression in locally advanced breast cancer samples that receive neoadjuvant treatment with doxorubicin were evaluated. Expression of TopoIIa was determined by immunohistochemistry in samples embedded in paraffin. Patients expressing TopoIIa were clustered according to the dose intensity of doxorubicin (≤ 24 or > 24 mg/m2/week). Survival curves were determined by Kaplan-Meier test and the comparations with the Logrank test. Results: 109 samples were evaluated. 40/109 (36.7%) over express TopoIIa, there was no differences in clinical characteristics in both groups. In patients TopoIIa positive, the median to age was 47 years (range: 33–74), Postmenopausal 30/40 (75%), ductal carcinoma 37/40 (92.5%) and lobulillar carcinoma 3/40 (7.5%). Positive estrogen receptors: 18/40 (45%) and positive progesterone receptor: 11/40 (27.5%). High proliferation index of expression of Ki-67 (≥40%) in 21/35 (40%) and HER2 positive in 10/37 (27%). Dose intensity of doxorubicin: ≤ 24 mg/m2/week in 15/40 (37.5%) and > 24 mg/m2/week in 25/40 (62.5%). Results of efficacy are showed in the follow table: Conclusions: Patients with locally advanced breast cancer and over expression of TopoIIa receiving a dose intensity > 24 mg/m2/week present a better survival than patients receiving lower dose intensities. Total < 24 mg/m2/week > 24 mg/m2/week p DFS Median 30 months 16 months 63 months 0.010 5 years OS 38% 13% 50% Median 32 months 27 months 57 months 0.027 5 years 35 % 14 % 45 % No significant financial relationships to disclose.

Dose and dose intensity effect of adjuvant anthracycline-based chemotherapy in early breast cancer: a retrospective analysis.

The purpose of this study was to determine the importance of the dose of adjuvant chemotherapy in patients with breast cancer, and to determine which variables had influence on the dose of chemotherapy received. We reviewed the records of 196 patients with node-positive breast carcinoma that were treated with anthracycline-based adjuvant chemotherapy. We analyzed the influence on treatment efficacy of the dose of anthracyclines (total dose and dose intensity), and a multivariate analysis was performed to identify independent prognostic factors of chemotherapy total dose. There were no differences in disease-free survival or overall survival between patients who received doses below or above the median total dose and median dose intensity of anthracyclines. A positive correlation was observed between the total dose of anthracycline received and the number of axillary lymph nodes. The clinical outcome of patients with node-positive breast cancer receiving adjuvant anthracycline-based chemotherapy is not affected by the amount of chemotherapy delivered. There exists a clinical practice of administering more chemotherapy in patients with poorer prognosis, which does not result in better therapeutic outcomes.

The impact of chemotherapy dose density and dose intensity on breast cancer outcome: what have we learned?

Optimising chemotherapy dose density and dose intensity are strategies aimed at improving outcomes in adjuvant therapy for patients with breast cancer. There are, in theory, at least five models allowing the delivery of a higher overall drug dose intensity. These are reviewed in this article and vary according to three main variables: the dose per course, the interval between doses and the total cumulative dose. Cyclophosphamide, anthracyclines and taxanes are among the most active agents for the treatment of breast cancer and, as such, they have been or are currently the focus of prospective, randomised clinical trials testing some of these dose-intensity models in the adjuvant setting. The results of recent trials suggest that anthracyclines, but not cyclophosphamide, are associated with better outcomes if used at higher doses per course and at higher cumulative doses. However, care has to be taken with premenopausal women where an increased dose of anthracycline per course but a reduced cumulative dose appears to produce a worse outcome. Moreover, decreasing the interval between doses, for anthracyclines and cyclophosphamide, does not seem to provide, so far, additional benefits for women with locally advanced breast cancer. This approach is not feasible with docetaxel, since an increase in dose density induces unwanted side-effects. These results represent our current state of knowledge, but clinical trials are being performed to evaluate further the effect of dose intensity, dose density and cumulative dose of key therapeutic agents on patient outcomes.

80 Dose-intensification of V-ICE chemotherapy with GM-CSF in small cell lung cancer (SCLC)—A prospective randomised study of 301 patients

Patients (pts) with SCLC and ≤ 3 adverse prognostic features (Manchester system) were randomised in a multicentre prospective study to 6 courses of VICE chemotherapy (ifosfamide 5 g/m2, carboplatin 300 mg/m2, etoposide 120 mg/m2 iv dl, 2 & 240 mg/m2po d3, vincristine 0.5 mg/m2 d14) every 3 or 4 weeks (“intensified” & “standard” arms respectively). Pts received 14 days of granulocyte-macrophage colonystimulating factor (GM-CSF) or placebo (250 μg/m2/d) between each course in a double-blind fashion. Endpoints are to determine the effects of dose-intensity and GM-CSF on outcome. 301 pts were entered from 17 centres in Europe (70% from 4 centres) up to 1/94. Sixty-three percent had ≤ 1 adverse prognostic feature and 41% had extensive stage disease (similar distribution in “fixed” and “intensive” arms). Overall, 30% greater dose-intensity was administered to pts in the “intensive” arm. Preliminary outcome assessments are: “fixed” arm—documented sepsis—28 pts, OR 76% (52% CR), 8—month survival 63%; “intensive” arm—documented sepsis-11 pts, OR 87% (47% CR), 8—month survival 75%. Detailed outcome analysis with assessment of the effects of GM-CSF will be performed in 6/95 with a minimum follow up of 1 year.

Treatment of advanced-stage Hodgkin's disease: alternating noncrossresistant MOPP/CABS is not superior to MOPP.

One hundred twenty-five assessable patients with advanced-stage Hodgkin's disease were randomized to receive mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) or MOPP alternating with lomustine (CCNU), doxorubicin, bleomycin, and streptozocin (CABS). The median follow-up is 7.7 years. The complete response rate was 60 of 66 MOPP-treated patients (91%) and 54 of 59 MOPP/CABS-treated patients (92%) (difference not significant). The level of the disease-free survival curve at longest follow-up is 65% for MOPP-treated patients and 72% for MOPP/CABS-treated patients (difference not significant). The overall survival at 12 years is projected at 68% for MOPP-treated patients and 54% for MOPP/CABS-treated patients (difference not significant). Thus, there were no significant differences in efficacy between MOPP and MOPP/CABS. However, MOPP/CABS was more emetogenic than MOPP, and four MOPP/CABS-treated patients went on to develop secondary acute leukemia. No MOPP-treated patients developed leukemia. High initial erythrocyte sedimentation rate (ESR) and high platelet counts adversely affected treatment outcome. MOPP-treated patients who received greater than 81% of the projected dose intensity of vincristine over the first three cycles had significantly improved disease-free survival rates over those receiving less than 81%. MOPP/CABS-treated patients who received greater than 82% of the projected dose intensity of vincristine had significantly better overall survival than those who received less than 82%. Disease-free survival on both arms was significantly better in patients who received greater than 84% of the projected dose intensity of all agents. The effect of dose intensity was particularly apparent in patients with poor prognostic factors where those who received greater than 84% of the projected dose intensity of all agents had significantly improved disease-free and overall survival.

High dose intensity combination chemotherapy for advanced epithelial ovarian carcinoma: results of a pilot study

Retrospective studies have recently demonstrated a significant correlation between dose intensity of chemotherapy and response rates and survival in various diseases including epithelial ovarian carcinoma. As part of a proposed randomised trial to assess the effect of dose intensity on outcome in ovarian carcinoma, a pilot study has been undertaken to determine the toxicity and efficacy of the high intensity therapy. Nineteen patients with advanced ovarian carcinoma received initial treatment with cisplatin 120 mg m-2 i.v. day 1, and cyclophosphamide 1,000 mg-2 i.v. day 1, given at 21-day intervals for six cycles. The average relative dose intensity of this therapy is 1.14 when compared with the CHAP regimen. Severe toxicity was experienced by most patients. The median received average relative dose intensity was 0.90, with only one patient receiving treatment to the proposed intensity. Randomised studies of the effect of dose intensity in ovarian carcinoma are essential, but an initial step must be to assess whether the proposed high dose treatment can be delivered.

Effects of dose-rate and protraction: a symposium. I. Patterns of response to whole-body irradiation: the effect of dose intensity and exposure time on duration of life and tumour production.

There seems to be a basic difference of approach between those who are trying to improve radiotherapy and those who are trying to understand the ways in which unwanted exposure to radiation can lead to harm. The aim of the therapist is often to destroy something selectively, be it a malignant tumour or some other pathological process, and what matters is how completely the pathological lesion can be eradicated. The basic mechanisms which are of fundamental importance are the mechanisms by which radiation kills cells or prevents their further division, whether by interfering with their ability to survive the ordeal of mitosis (Spear, 1953) or by changing their habit of growth in the direction of increasing differentiation (Glücksman, 1952). When considering the harmful effect of unwanted irradiation, however, it is not of primary importance what the mechanisms of cell death or of interference with cell division are, or how many cells are so affected, provided that some cells survive and can multiply to replace those which are missing. The survival and multiplication are the primarily important phenomena and these are basic physiological properties which may not be directly affected by the radiation exposure at all. This is the most striking lesson to be learnt from experimental work with single large doses of radiation where the patterns of response of different organs, such as intestine, bone marrow, testes and ovary, depend so clearly on their intrinsic physiological properties.